Nonpathogenic CCR2-tropic SIVrcm after serial passage and its effect on SIVmac infection of Indian rhesus macaques

The natural host of SIVrcm is the red-capped mangabey (Cercocebus torquatus torquatus). Although this virus infects macaques and human PBMCs, its pathogenic potential is unknown. We serially passaged SIVrcm through 9 rhesus macaques to assess its potential for virulence. SIVrcm infected all macaques with peak viremia 2 weeks postinfection yet viral loads decreased to undetectable levels about one month after inoculation. Remarkably, SIVrcm replication and virulence did not increase following 7 serial passages. While CD4+ T cells in the gut were decreased in early infection, proportions of memory CD4+CCR5+ T cells were not affected. Three SIVrcm-infected macaques were subsequently challenged with SIVmac251 to assess the potential for superinfection. Interestingly, animals previously infected with SIVrcm had 100 fold lower levels of SIVmac251 in plasma compared to naive animals inoculated with SIVmac251. These results suggest that SIVrcm is nonpathogenic and may be useful for examining effective immune responses in SIV infection.     

Depressive symptoms in patients with obstructive sleep apnea: biological mechanistic pathways

This study examined the association between depressive symptoms, as well as depressive symptom dimensions, and three candidate biological pathways linking them to Obstructive sleep apnea (OSA): (1) inflammation; (2) circulating leptin; and (3) intermittent hypoxemia. Participants included 181 obese adults with moderate-to-severe OSA enrolled in the Cardiovascular Consequences of Sleep Apnea (COSA) trial. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI-II). We assessed inflammation using C-reactive protein levels (CRP), circulating leptin by radioimmunoassay using a double antibody/PEG assay, and intermittent hypoxemia by the percentage of sleep time each patient had below 90% oxyhemoglobin saturation. We found no significant associations between BDI-II total or cognitive scores and CRP, leptin, or percentage of sleep time below 90% oxyhemoglobin saturation after controlling for relevant confounding factors. Somatic symptoms, however, were positively associated with percentage of sleep time below 90% saturation (β = 0.202, P = 0.032), but not with CRP or circulating leptin in adjusted models. Another significant predictor of depressive symptoms included sleep efficiency (β_{BDI Total} = ?0.230, P = 0.003; β_cognitive = ?0.173, P = 0.030 (β_somatic = -0.255, P = 0.001). In patients with moderate-to-severe OSA, intermittent hypoxia may play a role in somatic rather than cognitive or total depressive symptoms.     

Age-related increase of prostaglandin D2 synthase concentration and glycation in ovine cerebrospinal fluid

Prostaglandin D₂ synthase (PGDS) is a glycoprotein that is exclusively brain derived and is one of the most abundant proteins in the cerebrospinal fluid (CSF). Due to its high CSF specificity, it can be used as a tool for the diagnosis of central nervous system (CNS) disorders. However, several studies have yielded contradictory CSF PGDS concentrations in various CNS neurodegenerative disorders. Sheep CSF samples from different ages were used in this study and 2-dimensional electrophoresis (2-DE) was applied in PGDS identification and concentration calculation. SYPRO Ruby Protein Gel Stain was the staining method used to stain the 2-DE gel protein spots. Pro-Q Emerald 488 Staining for Glycoproteins was used for the staining of glycoproteins. A total of nine PGDS isoforms were identified and CSF total PGDS concentration was calculated to increase linearly by 44% from young (0.9323 ± 0.0637 mg dL⁻¹) to old (1.3669 ± 0.0558 mg dL⁻¹). However, the proportion of CSF total PGDS as a percentage of CSF total protein was discovered to decrease exponentially with age. This was due to the influence of larger age-related increase in CSF albumin concentration (>200% from young to old) as albumin is the most abundant protein in the CSF (>60% of total CSF proteins). Active deglycosylation was not observed in PGDS isoforms during healthy ageing. Some PGDS isoforms were observed to have age-related increase in glycation. These findings suggest that CSF PGDS concentration is increased during healthy ageing and must be taken into consideration when using PGDS as a potential biomarker in diagnosing CNS neurodegenerative disorders. Whether age-related increase in the glycation of some CSF PGDS isoforms will result in detrimental effects on the PGDS protein function needs further investigations.     

Polymorphisms in apoptosis- and proliferation-related genes, ionizing radiation exposure, and risk of breast cancer among U.S. Radiologic Technologists.

BACKGROUND: Although genes involved in apoptosis pathways and DNA repair pathways are both essential for maintaining genomic integrity, genetic variants in DNA repair have been thought to increase susceptibility to radiation carcinogenesis, but similar hypotheses have not generally been raised about apoptosis genes. For this reason, potential modification of the relationship between ionizing radiation exposure and breast cancer risk by polymorphic apoptosis gene variants have not been investigated among radiation-exposed women. METHODS: In a case-control study of 859 cases and 1,083 controls within the U.S. Radiologic Technologists cohort, we assessed breast cancer risk with respect to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation. Using carefully reconstructed cumulative breast dose estimates from occupational and personal diagnostic ionizing radiation, we also investigated the joint effects of these polymorphisms on the risk of breast cancer. RESULTS: In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8 D302H [rs1045485, odds ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8]. We found a significantly increased breast cancer risk with increasing minor alleles for IL1A A114S (rs17561); heterozygote OR 1.2 (95% CI, 1.0-1.4) and homozygote OR 1.5 (95% CI, 1.1-2.0), P(trend) = 0.008. Assuming a dominant genetic model, IL1A A114S significantly modified the dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational dose (P(interaction) = 0.004). CONCLUSION: The U.S. Radiologic Technologists breast cancer study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure to the breast using detailed occupational and personal diagnostic dose data. We found evidence of effect modification of the radiation and breast cancer dose-response relationship that should be confirmed in studies with more cases and controls and quantified radiation breast doses in the low-to-moderate range.     

Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Protein S deficiency is a recognized risk factor for venous thrombosis. Of all the inherited thrombophilic conditions, it remains the most difficult to diagnose because of phenotypic variability, which can lead to inconclusive results. We have overcome this problem by studying a cohort of patients from a single center where the diagnosis was confirmed at the genetic level. Twenty-eight index patients with protein S deficiency and a PROS1 gene defect were studied, together with 109 first-degree relatives. To avoid selection bias, we confined analysis of total and free protein S levels and thrombotic risk to the patients' relatives. In this group of relatives, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis (95% confidence interval, 1. 5-16.8) than those with a normal PROS1 gene and no other recognized thrombophilic defect. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice-site or major structural defects in the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. We conclude that persons with PROS1 gene defects and protein S deficiency are at increased risk of thrombosis and that free protein S estimation offers the most reliable way of diagnosing the deficiency. (Blood. 2000;95:1935-1941)     

Lean body mass changes in cancer patients with weight loss

BACKGROUND AND AIMS: Metabolic measurements (e.g. resting energy expenditure) are adjusted to lean body mass to account for body composition differences. Usually lean body mass is estimated from total body water. However, this may be compromised in weight-losing cancer patients owing to alterations in the degree of hydration of the lean body mass. This study examined the relationship between two independent estimates of lean body mass in healthy subjects and cancer patients with weight loss. METHODS AND RESULTS: Height, weight, total body water and total body potassium were measured in healthy subjects (n=9) and weight losing cancer patients (n=13). They were similar in terms of age and gender. However, the cancer group had a significantly lower percentage ideal body weight (P<0.001). The measured total body water values in both groups were similar to those predicted. In contrast, measured total body potassium values in the cancer group were significantly lower than predicted (P<0.001). There was a correlation between the ratio of measured lean body mass (water/lean bodymass (potassium) and the percentage weight loss (r=0.698, P<0.001). CONCLUSIONS: These results suggest that total body water significantly overestimates metabolically active tissue in weight-losing cancer patients and therefore its use as the basis for metabolic requirements in this group of patients is questionable.     

Big issues, small systems: managing with information in medical research

This subject of this article is the design of a database system for handling files related to the work of the Molecular Genetics Department of the International Blood Group Reference Laboratory. It examines specialist information needs identified within this organization and it indicates how the design of the Rhesus Information Tracking System was able to meet current needs. Rapid Applications Development prototyping forms the basis of the investigation, linked to interview, questionnaire, and observation techniques in order to establish requirements for interoperability. In particular, the place of this specialist database within the much broader information strategy of the National Blood Service will be examined. This unique situation is analogous to management activities in broader environments and a number of generic issues are highlighted by the research.     

Structure and evolution of echo dense lesions in the neonatal brain. A combined ultrasound and necropsy study.

Sixty seven of 216 infants weighing less than 2 kg at birth had cerebral lesions on ultrasonic scanning. Eight of 17 who had periventricular leukomalacia, with or without subependymal or intraventricular haemorrhage, or both, died. These and one larger baby were the subject of a combined ultrasound, and where appropriate, necropsy study. There was excellent correlation between the ultrasound and necropsy findings, only some of the earlier lesions of periventricular leukomalacia being missed by ultrasound. The data suggest it is now possible to distinguish periventricular leukomalacia and subependymal/intraventricular haemorrhage by ultrasound, that both lesions may be present in the same brain, that apparent parenchymal extension of an intraventricular haemorrhage is more probably the result of haemorrhage into ischaemic periventricular tissue, and that the term ''periventricular haemorrhage'' should be abandoned since it confuses two lesions of differing aetiology and differing clinical importance. Future advances in neonatal brain ultrasound depend on accurate assessment of both the nature and site of lesions within the cerebral hemispheres and ventricular system since the interpretation of these parameters is of critical importance.